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The dynamics of T cells during persistent Staphylococcus aureus infection: from antigen-reactivity to in vivo anergy.

Ziegler C, Goldmann O, Hobeika E, Geffers R, Peters G, Medina E - EMBO Mol Med (2011)

Bottom Line: The mechanisms by which persistent infections are maintained involve both bacterial escape strategies and modulation of the host immune response.So far, the investigations in this area have focused on strategies used by S. aureus to persist within the host.The T cell hyporesponsiveness was reverted by co-stimulation with the phorbol ester PMA, an activator of protein kinase C, suggesting that a failure in the T cell receptor (TCR)-proximal signalling events underlie the hyporesponsive phenotype.

View Article: PubMed Central - PubMed

Affiliation: Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.

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T cells are critical for the control of S. aureus proliferation during a persistent infectionDot plot flow cytometry analysis of splenic CD4+ and CD8+ T cells from RAG2−/− mice prior (ii) and 56 days after (iii) reconstitution with purified T cells (5 × 105) isolated from the spleen of C57BL/6 donor mice (i). Dot plot analysis of splenic B cells from T cells-reconstituted RAG−/− mice is shown in (iv).Bacterial loads in the kidneys of C57BL/6 mice (black bar) and groups of RAG2−/− mice (white bars), non-reconstituted or reconstituted with either purified T cells or with the non-T cell fraction at 56 days after intravenous inoculation with S. aureus. Bars represent the mean ± SD of four mice per group. One representative experiment of three independent experiments is presented. **p < 0.01 and ***p < 0.001.
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fig07: T cells are critical for the control of S. aureus proliferation during a persistent infectionDot plot flow cytometry analysis of splenic CD4+ and CD8+ T cells from RAG2−/− mice prior (ii) and 56 days after (iii) reconstitution with purified T cells (5 × 105) isolated from the spleen of C57BL/6 donor mice (i). Dot plot analysis of splenic B cells from T cells-reconstituted RAG−/− mice is shown in (iv).Bacterial loads in the kidneys of C57BL/6 mice (black bar) and groups of RAG2−/− mice (white bars), non-reconstituted or reconstituted with either purified T cells or with the non-T cell fraction at 56 days after intravenous inoculation with S. aureus. Bars represent the mean ± SD of four mice per group. One representative experiment of three independent experiments is presented. **p < 0.01 and ***p < 0.001.

Mentions: To determine the relevance of B cells for the containment of S. aureus during the persistent infection, we transferred B cells from C57BL/6 donor mice (Fig 6Ci) into RAG2−/− recipient mice (Fig 6Cii). The purity of the transferred B cells was ∼97% (Fig S8 of Supporting information). The efficiency of long-term B cell reconstitution was ∼50% and was determined by assessing the expression of CD45R/B220 and CD79b (component of the BCR highly expressed on mature B cells) on splenocytes of reconstituted RAG2−/− mice after the completion of the experiment (day 56 p.i.; Fig 6Ciii). The carryover of CD4+ or CD8+ T cells were <1% in the B cell-reconstituted RAG2−/− mice (Fig 6iv). The transfer of purified B cells, however, did not improve their capacity to restrain S. aureus proliferation during persistent infection (Fig 6D). Similar results were obtained when primed B cells isolated from S. aureus-infected mice were used for the reconstitution of the RAG2−/− mice (data not shown). Conversely, RAG−/− mice adoptively transferred with the non-B cell splenocyte fraction were as effective as immunocompetent C57BL/6 mice at controlling S. aureus during the persistent infection (Fig 6D) suggesting that T cells rather than B cells were responsible for this effect. To confirm this assumption, purified T cells (CD4+ plus CD8+ cells) from C57BL/6 mice (Fig 7Ai) were adoptively transferred into RAG2−/− mice (Fig 7A ii) prior to S. aureus infection (Fig 7). The purity of the transferred T cells was ∼98% (Fig S9 of Supporting information). The efficiency of reconstitution was ∼60% for CD4+ and ∼50% for CD8+ T cells (determined at day 56 p.i.; Fig 7Aiii). No B cells were detected in the T cells-reconstituted RAG2−/− mice (Fig 7Aiv). Adoptive transfer of T cells significantly improved the capacity of RAG2−/− mice to control S. aureus during persistent infection to levels seen in immunocompetent C57BL/6 mice (Fig 7B). In contrast, adoptive transfer of the non-T cell splenocyte fraction into RAG−/− had no beneficial effect in the ability of recipient RAG2−/− mice to control the staphylococcal infection (Fig 7B). These observations support the critical role of T cells for limiting bacterial proliferation during persistent infection.


The dynamics of T cells during persistent Staphylococcus aureus infection: from antigen-reactivity to in vivo anergy.

Ziegler C, Goldmann O, Hobeika E, Geffers R, Peters G, Medina E - EMBO Mol Med (2011)

T cells are critical for the control of S. aureus proliferation during a persistent infectionDot plot flow cytometry analysis of splenic CD4+ and CD8+ T cells from RAG2−/− mice prior (ii) and 56 days after (iii) reconstitution with purified T cells (5 × 105) isolated from the spleen of C57BL/6 donor mice (i). Dot plot analysis of splenic B cells from T cells-reconstituted RAG−/− mice is shown in (iv).Bacterial loads in the kidneys of C57BL/6 mice (black bar) and groups of RAG2−/− mice (white bars), non-reconstituted or reconstituted with either purified T cells or with the non-T cell fraction at 56 days after intravenous inoculation with S. aureus. Bars represent the mean ± SD of four mice per group. One representative experiment of three independent experiments is presented. **p < 0.01 and ***p < 0.001.
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fig07: T cells are critical for the control of S. aureus proliferation during a persistent infectionDot plot flow cytometry analysis of splenic CD4+ and CD8+ T cells from RAG2−/− mice prior (ii) and 56 days after (iii) reconstitution with purified T cells (5 × 105) isolated from the spleen of C57BL/6 donor mice (i). Dot plot analysis of splenic B cells from T cells-reconstituted RAG−/− mice is shown in (iv).Bacterial loads in the kidneys of C57BL/6 mice (black bar) and groups of RAG2−/− mice (white bars), non-reconstituted or reconstituted with either purified T cells or with the non-T cell fraction at 56 days after intravenous inoculation with S. aureus. Bars represent the mean ± SD of four mice per group. One representative experiment of three independent experiments is presented. **p < 0.01 and ***p < 0.001.
Mentions: To determine the relevance of B cells for the containment of S. aureus during the persistent infection, we transferred B cells from C57BL/6 donor mice (Fig 6Ci) into RAG2−/− recipient mice (Fig 6Cii). The purity of the transferred B cells was ∼97% (Fig S8 of Supporting information). The efficiency of long-term B cell reconstitution was ∼50% and was determined by assessing the expression of CD45R/B220 and CD79b (component of the BCR highly expressed on mature B cells) on splenocytes of reconstituted RAG2−/− mice after the completion of the experiment (day 56 p.i.; Fig 6Ciii). The carryover of CD4+ or CD8+ T cells were <1% in the B cell-reconstituted RAG2−/− mice (Fig 6iv). The transfer of purified B cells, however, did not improve their capacity to restrain S. aureus proliferation during persistent infection (Fig 6D). Similar results were obtained when primed B cells isolated from S. aureus-infected mice were used for the reconstitution of the RAG2−/− mice (data not shown). Conversely, RAG−/− mice adoptively transferred with the non-B cell splenocyte fraction were as effective as immunocompetent C57BL/6 mice at controlling S. aureus during the persistent infection (Fig 6D) suggesting that T cells rather than B cells were responsible for this effect. To confirm this assumption, purified T cells (CD4+ plus CD8+ cells) from C57BL/6 mice (Fig 7Ai) were adoptively transferred into RAG2−/− mice (Fig 7A ii) prior to S. aureus infection (Fig 7). The purity of the transferred T cells was ∼98% (Fig S9 of Supporting information). The efficiency of reconstitution was ∼60% for CD4+ and ∼50% for CD8+ T cells (determined at day 56 p.i.; Fig 7Aiii). No B cells were detected in the T cells-reconstituted RAG2−/− mice (Fig 7Aiv). Adoptive transfer of T cells significantly improved the capacity of RAG2−/− mice to control S. aureus during persistent infection to levels seen in immunocompetent C57BL/6 mice (Fig 7B). In contrast, adoptive transfer of the non-T cell splenocyte fraction into RAG−/− had no beneficial effect in the ability of recipient RAG2−/− mice to control the staphylococcal infection (Fig 7B). These observations support the critical role of T cells for limiting bacterial proliferation during persistent infection.

Bottom Line: The mechanisms by which persistent infections are maintained involve both bacterial escape strategies and modulation of the host immune response.So far, the investigations in this area have focused on strategies used by S. aureus to persist within the host.The T cell hyporesponsiveness was reverted by co-stimulation with the phorbol ester PMA, an activator of protein kinase C, suggesting that a failure in the T cell receptor (TCR)-proximal signalling events underlie the hyporesponsive phenotype.

View Article: PubMed Central - PubMed

Affiliation: Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.

Show MeSH
Related in: MedlinePlus